The cellular and molecular pathways involved in the regulatory effects of proinflammatory and immunoregulatory cytokines on human immunodeficiency virus (HIV) expression/replication were investigated. The complex interactions between various cytokines, such as interleukin (IL)-10 and tumor necrosis factor (TNF)-alpha or IL-6, and between cytokines and other cell-mediated signals, such as inducers of cellular differentiation, with regard to regulation of HIV expression were demonstrated in primary monocyte-derived macrophages (MDM) and/or in chronically infected cell lines. Investigation of the molecular basis for these effects demonstrated multiple mechanisms, including transcriptional and post-transcriptional events, whereby cellular factors influence HIV expression. Autocrine/paracrine stimulation of HIV expression by endogenous cytokines was demonstrated in MDM and primary peripheral blood mononuclear cells. In these systems, inhibition of cytokine secretion and/or activity by physiologic agents, such as IL-10, soluble cytokine receptors or antagonists, or by pharmacologic agents, such as pentoxifylline, resulted in significant suppression of HIV replication. Pentoxifylline was also tested in vivo in the simian immunodeficiency virus (SIV)-infected macaque animal model. Although no inhibition of acute phase-related TNF-` production was observed, pentoxifylline-treated animals exhibited lower plasma and cell-associated viremia, lower apoptosis in the lymph node, and possibly delayed disease progression. Novel mechanisms of cell-mediated regulation of HIV expression/replication were demonstrated using PBMC or lymph node (LN) cells from HIV-infected individuals or in chronically infected cell lines. IL-12 was found to allow isolation of HIV from unfractionated PBMC or LN cells in the presence of CD8-mediated viral suppressive activity; preliminary data suggest that IL-12 can interfere or bypass CD8-mediated suppression. Triggering of the CD30 molecule, a newly described member of the TNF-alpha receptor family, was found to potently induce HIV expression in chronically infected cells, most likely by activating the cellular transcription factor NF-kappaB. These studies indicate that endogenous cytokines may play a major role in the pathogenesis of HIV disease. Such information may prove useful in the design of therapeutic strategies.